Li Yan-Ping, Shan Guang-Zhi, Peng Zong-Gen, Zhu Jian-Hua, Meng Shuai, Zhang Tian, Gao Lin-Yan, Tao Pei-Zhen, Gao Rong-Mei, Li Yu-Huan, Jiang Jian-Dong, Li Zhuo-Rong
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Antivir Chem Chemother. 2010 Aug 11;20(6):259-68. doi: 10.3851/IMP1631.
Previous studies have suggested that geldanamycin (GA) inhibits the replication of several viruses in vitro. Here, we aimed to synthesize and evaluate the antiviral activity of 17-amino-17-demethoxygeldanamycin derivatives.
A series of 17-substituted and 17-,19-disubstituted GA derivatives were screened for antiviral activities against eight different viral strains, including herpesvirus, hepatitis virus, retrovirus and picornavirus.
Most of the tested compounds showed inhibitory activity against the viruses and showed reduced cytotoxicity in vitro as compared with the parent compound GA. In vivo efficacy evaluation results showed that compound 6 noticeably inhibited duckling hepatitis B virus DNA replication in duckling serum after oral administration. Viral rebound did not occur after termination of the treatment. The modified GA derivatives also showed median lethal dose values that were higher than that of the parent GA in mice intraperitoneally treated with the study compounds.
Targeting heat-shock protein 90 could be a new antiviral approach that is not prone to the development of drug resistance. The 17-amino-17-demethoxygeldanamycin derivatives could be novel agents with potential antiviral activity.
先前的研究表明，格尔德霉素（GA）在体外可抑制多种病毒的复制。在此，我们旨在合成并评估17-氨基-17-去甲氧基格尔德霉素衍生物的抗病毒活性。
筛选了一系列17-取代和17,19-二取代的GA衍生物，检测其对八种不同病毒株的抗病毒活性，这些病毒株包括疱疹病毒、肝炎病毒、逆转录病毒和小RNA病毒。
大多数受试化合物对病毒显示出抑制活性，并且与母体化合物GA相比，在体外表现出更低的细胞毒性。体内疗效评估结果显示，化合物6口服给药后可显著抑制雏鸭血清中鸭乙型肝炎病毒DNA的复制。治疗终止后未出现病毒反弹。在用研究化合物腹腔注射处理的小鼠中，修饰后的GA衍生物的半数致死剂量值也高于母体GA。
靶向热休克蛋白90可能是一种不易产生耐药性的新型抗病毒方法。17-氨基-17-去甲氧基格尔德霉素衍生物可能是具有潜在抗病毒活性的新型药物。
